Feds lead investment in antimicrobial resistance, but more private help is needed, BARDA says

In an editorial published Saturday, The Lancet noted that strategies to improve antimicrobial resistance (AMR) “have been consistently recommended.”

However, “[i]nnovation has been extremely slow,” the editorial continued. “Vaccines are available for only one of the six leading pathogens … The clinical pipeline for antibiotics is too small to tackle the increasing emergence and spread of AMR.”

“National leaders now have an obligation to move AMR to a higher position in their political agendas,” the editorialists argued. “Research efforts should be accelerated to address knowledge and innovation gaps and to inform policy and practices.”

The day before the editorial’s publication, MedPage Today spoke with Chris Houchens, PhD, director of the division of Chemical, Biological, Radiological, and Nuclear (CBRN) Medical Countermeasures for the Biomedical Advanced Research and Development Authority (BARDA). We discussed BARDA’s investments in addressing AMR, the potential of vaccines for AMR, and why private investment in this space lags, among other issues.

The following is an edited version of our conversation:

Give me your assessment on the AMR issue. I’ve heard it referred to as the next big pandemic; I’m wondering if you agree about that.

Houchens: I would agree it is the next pandemic. In fact, it’s a pandemic that’s already occurring [and] responsible for, I think, close to 23,000 deaths every year in the United States.

It’s going to be very challenging to ever develop that definitive antibiotic that addresses bacterial infection, all the different indications which the bug is not going to figure out how to get around.

Is it a pandemic of COVID-19 proportions? Or is it ever going to be as transmissible as Ebola? Probably not.

You’re in a very, very precarious state, that there is very limited private equity support. There is not a return on investment, because … people that are taking these drugs, they take them for 2 or 3 weeks at a time, rather than for the rest of their lives. It’s a small population that takes them, there’s generics on the market, and these drugs are going to fail in 4 or 5 years. [But] likely at some point you or somebody you know, somebody that’s close to you, is going to be impacted by this. It’s almost like global warming.

What do you think it would take? Or is it even possible to get more pharmaceutical investment in the space?

Houchens: There are a lot of private equity investors who are happy to invest in technologies and products and things like that, that serve a public good. They don’t have to make a lot of money doing it, but they don’t want to lose money doing it, either. A new antibiotic, it’s going to require $1 billion in investment to get it to the market, then those investors are going to want to see at least $2 billion in return in sales.

It’s going to require that antibiotics are appropriately priced or reimbursed, whether it’s through changes in how CMS reimburses [or] another possibility is that companies that develop products, they receive a payment from the government, companies getting a payment for the delivery of an approved antibiotic that would be commensurate with the value of that antibiotic and [investments] the company have made.

I have to make clear: I’m not endorsing the policies. I’m talking about some of the policies that have been discussed.

Give me a high-level summary of the major programs BARDA are working on within the space.

Houchens: There are three major investment areas. One is CARB-X. This is a partnership that we established in 2016 with Boston University. And it brought in other funders like NIH, the Wellcome Trust, the governments of the United Kingdom and Germany, and also the Gates Foundation.

CARB-X was established to support the early-stage research and development of antibiotics … up through phase 1 development — at which point then we transition to the BARDA portfolio, where we support all the way to product licensure. Then we have a third area that we use that’s called Project BioShield. That is to support the post-licensure activities.

We’re actually 6 years now since we established CARB-X. We’ve invested $200 million. Our other partners have provided an additional $300 million. Other investors have provided another $2.2 billion. Nine of those [funded products] have graduated from CARB-X. Nine other products have also entered phase 1 development. … Right now the project has 54 active programs [out of 92 programs over the last 6 years]. Our bet was a 5-year project, and the U.S. government has made a commitment to continue CARB-X for another 10 years. Nine [products] entered clinical trials. We picked two up into our BARDA portfolio, into our clinical development portfolio.

So, does that mean we can expect those to be on the market at some point in the near future?

Houchens: At some point? Absolutely. The genesis of CARB-X was … gaps between discovery of a new antibiotic and getting it into clinical development, where there wasn’t a lot of accessibility. So, you did not see a lot of candidates coming through that early phase of development.

That brings us to the BARDA clinical portfolio. We have had that [since] 2010. We also recognized that there’s a critical need for developments for … bacteria that are responsible for the majority of hospital infections. They’re responsible for secondary bacterial infections that are often going to accompany any sort of health emergency. And also, at the end of the day, the real goal is to make sure that we are making antibiotics available.

And over the past 11 years, 12 years, we’ve invested $1.6 billion in product development for AMR. We support 18 [novel candidates] in advanced development. Seven of those are in phase 3. We anticipate that we’ll probably get two new approvals in the next year. We have one product in phase 2 and we have five products in phase 1. We also have a number of products that are already out and available now in preclinical development.

We supported the development of three drugs backed by the FDA over the last few years. The problem is these companies that got [the] products went bankrupt soon after product approval.

[Note: BARDA has helped cultivate 33 AMR candidates, resulting in three FDA approvals, a spokesperson told MedPage Today in an email following the interview.]

The post-approval phase for antibiotics is very, very cost-intensive. So, the third phase of our investment [is] to buy a drug and put it into the stockpile. And that is company revenue that they can use in turn to go back and build their skills and build a margin. It allows the company to gain the ability to market that drug for the new diseases, these new indications.

We anticipate that we’re going to put out a call for proposals pretty soon that’s going to look for two new antibiotics that we can support as a target for BioShield.

How much can BARDA really do? And how much will these efforts really help when it comes to addressing the problem of AMR? How about outside of government? Are we relying almost entirely on government to end this problem?

Houchens: I’m sorry to say, but yeah. Until an antibiotic can be valued appropriately for the health system on the delivery of healthcare, I just don’t see that any other entity is going to put their money on the line. And that’s the state that we play in, which is addressing market failures.

When we were at the World Anti-Microbial Resistance Congress, there was a lot of talk about vaccines. Not a lot of information was shared there. So, I’m wondering what you know about the potential for a vaccine?

Houchens: I think that there’s value in vaccines. Now, there are not a lot of indications where you could [have] patient populations that are at very high risk for specific bacterial infections. There are some cases for the elderly population in healthcare settings, long-term care settings, that are more susceptible to Pseudomonas infections, for example.

You’re not going to have the same patient population as you do for a cardiovascular drug or diabetes drug. You’d have to conduct a study with maybe 50,000 to 100,000 individuals, just to ensure that you have enough patients who are likely to go on to get a bacterial infection. So, all those are the economic forces that are pushing against the development of vaccines. Now, there may be some situations where you could see the use of a vaccine and the evaluation of a vaccine, in a post-exposure prophylaxis study.

[One] way that we could evaluate new vaccines for bacterial infections is looking at situations where you have likely exposures and vaccinating those individually. But again, they’re very challenging studies, very expensive studies to conduct, on a very limited patient population.

Right. So, do you have any idea as to why some of these companies are looking at this?

Houchens: They’re hoping to be able to demonstrate some value that’s going to differentiate their vaccine. They’re really invested, it doesn’t cost a lot of money to do that clinical research and development. We’re talking tens of millions of dollars compared to hundreds of millions or a billion dollars for the clinical development [of new drugs]. So, it’s easier for you to get smaller investment from venture capital for some of these, what could be very transformational vaccines.

What you saw at the World Anti-Microbial Resistance Congress, you’re seeing early-stage research and development of the vaccines that is not very capital intensive.

Is there anything that you wanted to add, anything important you feel like I didn’t cover?

Houchens: It’s going to continue to collapse [baring major change]. And those healthcare providers are going to lose access to these life-saving drugs.